Sublingual and buccal film compositions

ABSTRACT

The present invention relates to products and methods for treatment of various symptoms in a patient, including treatment of pain suffered by a patient. The invention more particularly relates to self-supporting dosage forms which provide an active agent while providing sufficient buccal adhesion of the dosage form. Further, the present invention provides a dosage form which is useful in reducing the likelihood of diversion abuse of the active agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/155,100, filed Oct. 9, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/369,101, filed Dec. 5, 2016, which is acontinuation of U.S. patent application Ser. No. 14/196,082, filed Mar.4, 2014, which issued as U.S. Pat. No. 9,511,033, on Dec. 6, 2016, whichis a continuation of U.S. patent application Ser. No. 13/842,543, filedMar. 15, 2013, the entire contents of all of which are incorporated byreference herein.

FIELD OF THE INVENTION

The present invention relates to compositions, methods of manufacture,products and methods of use relating to films containing therapeuticactives. The invention more particularly relates to self-supportingdosage forms which provide an agonist acting alone or in combinationwith a buffer system to maximize therapeutic absorption of the agonist.Some embodiments also include an antagonist, with the buffer systemacting to minimize the absorption of the antagonist. Such compositionsare particularly useful for preventing misuse of the active whileproviding sufficient buccal adhesion of the dosage form.

BACKGROUND OF THE RELATED TECHNOLOGY

Oral administration of two therapeutic actives in a single dosage formcan be complex if the intention is to have one active absorbed into thebody and the other active remain substantially unabsorbed. For example,one active may be relatively soluble in the mouth at one pH, and theother active may be relatively insoluble at the same pH. Moreover, theabsorption kinetics of each therapeutic agent may be substantiallydifferent due to differing absorption of the charged and unchargedspecies. These factors represent some of the challenges in appropriatelyco-administering therapeutic agents.

Co-administration of therapeutic agents has many applications. Amongsuch areas of treatment include treating individuals who suffer frompain or other medical condition. Such individuals may have a tendency tosuffer from serious physical dependence on the therapeutic agent,resulting in potentially dangerous withdrawal effects when thetherapeutic agent is not administered to the individual. In order toprovide treatment to patients, it is known to provide a reduced level ofa therapeutic agent, which provides an effect of treating the condition,but does not provide the “high” that may be provided by the therapeuticagent. The drug provided may be an agonist or a partial agonist, whichmay provide a reduction in pain or other symptom that the patient isexperiencing. However, even though these therapeutic agents provide onlya low level of euphoric effect, they are capable of being abused by theindividuals parenterally. In such cases, it is desirable to provide acombination of the therapeutic agent with a second therapeutic agent,which may decrease the likelihood of diversion and abuse of the firstdrug. For example, it is known to provide a dosage of an antagonist incombination with the agonist or partial agonist. The narcotic antagonistbinds to a receptor in the brain to block the receptor, thus reducingthe effect of the agonist.

One such combination of narcotic agents has been marketed under thetrade name Suboxone® as an orally ingestible tablet. However, suchcombinations in tablet form have the potential for abuse. In someinstances, the patient who has been provided the drug may store thetablet in his mouth without swallowing the tablet, then later extractthe agonist from the tablet and inject the drug into an individual'sbody. Although certain antagonists (such as highly water-solubleantagonists) may be used to help reduce the ability to separate theagonist, the potential for abuse still exists. Further, incorporation ofan antagonist in combination with the pain-relieving agonist has beenfound to reduce side effects associated with administration of theagonist, such as constipation and other undesirable effects. It isdesired to provide a dosage that cannot be easily removed from the mouthonce it has been administered.

There is currently a need for an orally dissolvable film dosage formthat provides the desired absorption levels of the agonist andantagonist, while providing an adhesive effect in the mouth, renderingit difficult to remove once placed in the mouth and achieving optimumabsorption of the agonist while inhibiting absorption of the antagonist.

SUMMARY OF THE INVENTION

In one embodiment of the present invention, there is provided aself-supporting film dosage composition including: a polymeric carriermatrix; a therapeutically effective amount of an agonist or apharmaceutically acceptable salt thereof; and a buffer sufficient tomaximize the absorption of the agonist.

In another embodiment of the present invention, there is provided aself-supporting film dosage composition including a polymeric carriermatrix, a therapeutically effective amount of an agonist or apharmaceutically acceptable salt thereof, a buffer sufficient tomaximize the absorption of the agonist, and a chelator or antioxidant.In another embodiment of the present invention, there is provided aself-supporting film dosage composition including a polymeric carriermatrix, a therapeutically effective amount of an agonist or apharmaceutically acceptable salt thereof, a therapeutically effectiveamount of an antagonist or a pharmaceutically acceptable salt thereof,buffering system; and a chelator or an antioxidant, wherein saidbuffering system comprises a buffer capacity sufficient to inhibit theabsorption of said antagonist during the time which said composition isin the oral cavity of a user.

In another embodiment of the present invention, there is provided aself-supporting film dosage composition including: a polymeric carriermatrix; a therapeutically effective amount of an agonist or apharmaceutically acceptable salt thereof; a therapeutically effectiveamount of an antagonist or a pharmaceutically acceptable salt thereof;and a buffering system; where the buffering system possesses a buffercapacity sufficient to inhibit the absorption of the antagonist duringthe time which the composition is in the oral cavity of a user.

In still another embodiment of the present invention, there is provideda method of treatment, including the steps of: providing a film dosagecomposition including: a polymeric carrier matrix; a therapeuticallyeffective amount of an agonist or a pharmaceutically acceptable saltthereof; and a buffer in an amount sufficient to maximize the absorptionof the agonist; and administering the film dosage composition to apatient.

In other embodiments of the present invention, there is provided amethod of treatment, including the steps of: providing a film dosagecomposition including: a polymeric carrier matrix; a therapeuticallyeffective amount of an agonist or a pharmaceutically acceptable saltthereof; a therapeutically effective amount of an antagonist or apharmaceutically acceptable salt thereof; a first buffer in an amountsufficient to obtain a local pH of the agonist of about 4 to about 9; abuffer in an amount sufficient to obtain a local pH of the antagonist ofabout 2 to about 4; and administering the film dosage composition to auser.

In another embodiment of the present invention, there is provided aself-supporting film dosage composition including: a first regionincluding: a first polymeric matrix; a therapeutically effective amountof an agonist or a pharmaceutically acceptable salt thereof; and a firstbuffering system in an amount sufficient to optimize the absorption ofthe agonist; a second region including: a second polymeric matrix; atherapeutically effective amount of an antagonist; and a secondbuffering system in an amount sufficient to inhibit the absorption ofthe antagonist.

In a further embodiment of the present invention, there is provided anorally dissolving film formulation including a first region including atherapeutically effective amount of an agonist and second regionincluding a therapeutically effective amount of an antagonist, where theformulation provides an in vivo plasma profile having a Cmax of about0.868-6.94 ng/ml for the agonist and an in vivo plasma profile having aCmax of about 32.5-260 pg/ml for the antagonist.

In another embodiment of the present invention, there is provided aself-supporting film dosage composition including: a polymeric carriermatrix; a therapeutically effective amount of an agonist or apharmaceutically acceptable salt thereof; a therapeutically effectiveamount of an antagonist or a pharmaceutically acceptable salt thereof;and a buffering system sufficient to obtain a local pH of the antagonistof about 2 to about 4.

In an embodiment of the present invention, there is provided aself-supporting film dosage composition including: a polymeric carriermatrix; a therapeutically effective amount of an agonist or apharmaceutically acceptable salt thereof; a therapeutically effectiveamount of an antagonist or a pharmaceutically acceptable salt thereof;and a buffering system sufficient to inhibit absorption of theantagonist and optimize absorption of the agonist when the film dosagecomposition is placed in the mouth of a user.

In another embodiment of the present invention, there is provided aself-supporting film dosage composition including: a first regionincluding: a first polymeric matrix; a therapeutically effective amountof an agonist or a pharmaceutically acceptable salt thereof; and a firstbuffering system in an amount sufficient to optimize absorption of theagonist when the film dosage composition is placed in the mouth of auser; and a second region including: a second polymeric matrix; atherapeutically effective amount of an antagonist; and a secondbuffering system in an amount sufficient to inhibit absorption of theantagonist when the film dosage composition is placed in the mouth of auser.

In yet another embodiment of the present invention, there is provided aprocess of forming a film dosage composition including the steps of:casting a film-forming composition, the film-forming compositionincluding: a polymeric carrier matrix; a therapeutically effectiveamount of an agonist or a pharmaceutically acceptable salt thereof; atherapeutically effective amount of an antagonist or a pharmaceuticallyacceptable salt thereof; and a buffer in an amount sufficient tooptimize absorption of the agonist and sufficient to inhibit absorptionof the antagonist when the film dosage composition is placed in themouth of a user; and drying the film-forming composition to form aself-supporting film dosage composition.

In still another embodiment of the present invention, there is provideda method of treatment, including the steps of: providing a film dosagecomposition including: a polymeric carrier matrix; a therapeuticallyeffective amount of an agonist or a pharmaceutically acceptable saltthereof; a therapeutically effective amount of an antagonist or apharmaceutically acceptable salt thereof; and a buffering system in anamount sufficient to provide an in vivo plasma profile having a Cmax ofabout 0.624-5.638 ng/ml for the agonist and an in vivo plasma profilehaving a Cmax of less than 324 pg/ml for the antagonist; andadministering the film dosage composition to a user.

In another embodiment of the present invention, there is provided aself-supporting film dosage composition including: a first regionincluding: a first polymeric matrix; a therapeutically effective amountof an agonist or a pharmaceutically acceptable salt thereof; and a firstbuffering system in an amount sufficient to optimize the absorption ofthe agonist; a second region including: a second polymeric matrix; atherapeutically effective amount of an antagonist; and a secondbuffering system in an amount sufficient to inhibit the absorption ofthe antagonist; where the second region dissolves at a faster rate whenplaced in the oral cavity of the user than the first region.

In another embodiment of the invention, there is provided a process offorming a film dosage composition including the steps of: casting afirst film-forming composition, the first film-forming compositionincluding: a polymeric carrier matrix; a therapeutically effectiveamount of an agonist or a pharmaceutically acceptable salt thereof; anda buffer in an amount sufficient to optimize absorption of the agonistwhen the film dosage composition is placed in the mouth of a user;casting a second film-forming composition, the second film-formingcomposition including: a polymeric carrier matrix; a therapeuticallyeffective amount of an antagonist or a pharmaceutically acceptable saltthereof; and a buffer in an amount sufficient to inhibit absorption ofthe antagonist when the film dosage composition is placed in the mouthof a user; and laminating the first film-forming composition and thesecond film-forming composition together to form a self-supporting filmdosage composition.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a graph presenting the results of an EDTA concentrationstudy.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Definitions

As used herein, the term Cmax refers to the mean maximum plasmaconcentration after administration of the composition to a humansubject. As also used herein, the term AUC refers to the mean area underthe plasma concentration-time curve value after administration of thecompositions formed herein. As will be set forth in more detail below,the term “optimizing the absorption” does not necessarily refer toreaching the maximum absorption of the composition, and rather refers toreaching the optimum level of absorption at a given pH. The “optimum”absorption may be, for example, a level that provides a bioequivalentabsorption as administration of the currently available Suboxone®tablet. Thus, if a bioequivalent absorption to Suboxone® is desired, theCmax of buprenorphine may be about 0.67 to about 5.36 ng/ml at dosagesof from 2-16 mg buprenorphine at a given pH. Similarly, an “optimum” AUCof buprenorphine may be about 7.43 to about 59.46 hr*ng/ml at dosages offrom 2-16 mg buprenorphine at a given pH. As will be described in moredetail below, it has been surprisingly discovered that the absorption ofone particular agonist, buprenorphine, can provide an optimum absorptionat a local pH of about 3-4 as well as about 5.5-6.5. Thus, one may“optimize” the absorption of buprenorphine by providing a local pH ofabout 3-4 or about 5.5-6.5.

“Maximizing the absorption” refers to the maximum in vivo absorptionvalues achieved at a local pH of about 4 to about 9.

The term “local pH” refers to the local pH of the region of the carriermatrix immediately surrounding the active agent as the matrix hydratesand/or dissolves, for example, in the mouth of the user.

By “inhibiting” the absorption of an active, it is meant achieving ascomplete an ionization state of the active as possible, such that littleto none of the active is measurably absorbable. For example, at a localpH of 3-3.5, the Cmax of an active such as naloxone for dosage of 0.5 mgto 4.0 mg ranges from 32.5 to 260 pg/ml, and an AUC of naloxone fordosage of 0.5 mg to 4.0 mg ranges from 90.55 to 724.4 hr*pg/ml. It isunderstood that at a local pH lower than 3.0, further ionization wouldbe expected and thus result in lower absorption.

The term “bioequivalent” means obtaining 80% to 125% of the Cmax and AUCvalues for a given active in a different product. For example, assumingCmax and AUC values of buprenorphine for a commercially-availableSuboxone® tablet (containing 2 mg buprenorphine and 0.5 mg naloxone) are0.780 ng/ml and 6.789 hr*ng/ml, respectively, a bioequivalent productwould have a Cmax of buprenorphine in the range of 0.624-0.975 ng/ml,and an AUC value of buprenorphine of 5.431-8.486 hr*ng/ml.

It will be understood that the term “film” includes thin films, sheetsand wafers, in any shape, including rectangular, square, or otherdesired shape. The films described herein may be any desired thicknessand size such that it may be placed into the oral cavity of the user.For example, the films may have a relatively thin thickness of fromabout 0.1 to about 10 mils, or they may have a somewhat thickerthickness of from about 10 to about 30 mils. For some films, thethickness may be even larger, i.e., greater than about 30 mils. Filmsmay be in a single layer or they may be multi-layered, includinglaminated films.

Oral dissolving films generally fall into three main classes: fastdissolving, moderate dissolving and slow dissolving. Fast dissolvingfilms generally dissolve in about 1 second to about 30 seconds in themouth. Moderate dissolving films generally dissolve in about 1 to about30 minutes in the mouth, and slow dissolving films generally dissolve inmore than 30 minutes in the mouth. Fast dissolving films may consist oflow molecular weight hydrophilic polymers (i.e., polymers having amolecular weight between about 1,000 to 9,000, or polymers having amolecular weight below 200,000). In contrast, slow dissolving filmsgenerally have high molecular weight polymers (i.e., having a molecularweight in the millions).

Moderate dissolving films tend to fall in between the fast and slowdissolving films. Moderate dissolving films dissolve rather quickly, butalso have a good level of mucoadhesion. Moderate dissolving films arealso flexible, quickly wettable, and are typically non-irritating to theuser. For the instant invention, it is preferable to use films that fallbetween the categories of fast dissolving and moderate dissolving. Suchmoderate dissolving films provide a quick enough dissolution rate, mostdesirably between about 1 minute and about 20 minutes, while providingan acceptable mucoadhesion level such that the film is not easilyremovable once it is placed in the oral cavity of the user.

Inventive films described herein may include one or more agonists orpartial agonists. As used herein, the term “agonist” refers to achemical substance that is capable of providing a physiological responseor activity in the body of the user. The films described herein mayfurther include one or more antagonists. As used herein, the term“antagonist” refers to any chemical substance that acts within the bodyof the user to reduce the physiological activity of another chemicalsubstance. In some embodiments, an antagonist used herein may act toreduce and/or block the physiological activity of the agonist. Theactives may be water-soluble, or they may be water-insoluble. As usedherein, the term “water-soluble” refers to substances that are at leastpartially dissolvable in a solvent, including but not limited to water.The term “water-soluble” does not necessarily mean that the substance is100% dissolvable in the solvent. The term “water-insoluble” refers tosubstances that are not readily dissolvable in a solvent, including butnot limited to water. Solvents may include water, or alternatively mayinclude other polar solvents by themselves or in combination with water.

Inventive Films

The present invention relates to methods of treating pain or othersymptoms in an individual while limiting the potential for abuse of thetreatment. More desirably, the invention relates to the treatment ofphysical pain in an individual, for example by administration of ananalgesic or other pain-relieving therapeutic agent. One suchtherapeutic agent that is known to treat pain in individuals includes anagonist such as buprenorphine. However, buprenorphine is known to be apartial agonist and therefore can be abused, and as such it is desiredto combine buprenorphine with an antagonist, thereby lessening thepotential for abuse by parenteral injection. Such combination of drugsis currently provided via a product marketed under the trade nameSuboxone®, which is an orally dissolvable tablet. This tablet whichprovides a combination of buprenorphine (an opioid agonist) and naloxone(an opioid antagonist). However, even using an antagonist such asnaloxone may be abused by a user. Therefore, the present inventionprovides a method of treating pain or other symptoms in a patient byproviding an orally dissolvable film dosage, which provides abioequivalent effect to Suboxone®. The film dosage further preferablyprovides buccal adhesion while it is in the user's mouth, rendering itdifficult to remove after placement.

The film dosage composition preferably includes a polymeric carriermatrix. Any desired polymeric carrier matrix may be used, provided thatit is orally dissolvable. Desirably, the dosage should have enoughbioadhesion to not be easily removed and it should form a gel likestructure when administered. The orally consumable films are preferablymoderate-dissolving in the oral cavity and particularly suitable fordelivery of actives, although both fast and sustained releasecompositions are also among the various embodiments contemplated. Insome embodiments, as will be described in more detail below, theinventive combination may include films that have more than one region,where each region has a different dissolution profile.

The films used in the pharmaceutical products may be produced by acombination of at least one polymer and a solvent, optionally includingother fillers known in the art. The solvent may be water, a polarorganic solvent including, but not limited to, ethanol, isopropanol,acetone, or any combination thereof. In some embodiments, the solventmay be a non-polar organic solvent, such as methylene chloride. The filmmay be prepared by utilizing a selected casting or deposition method anda controlled drying process. For example, the film may be preparedthrough controlled drying processes, which include application of heatand/or radiation energy to the wet film matrix to form a visco-elasticstructure, thereby controlling the uniformity of content of the film.Such processes are described in more detail in commonly assigned U.S.Pat. No. 7,425,292, the contents of which are incorporated herein byreference in their entirety. Alternatively, the films may be extruded asdescribed in commonly assigned U.S. application Ser. No. 10/856,176,filed on May 28, 2004, and published as U.S. Patent Publication No.2005/0037055 A1, the contents of which are incorporated herein byreference in their entirety.

The polymer included in the films may be water-soluble, water-swellable,water-insoluble, or a combination of one or more either water-soluble,water-swellable or water-insoluble polymers. The polymer may includecellulose or a cellulose derivative. Specific examples of usefulwater-soluble polymers include, but are not limited to, polyethyleneoxide, pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose,hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose,polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum,tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid,methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin,and combinations thereof. Specific examples of useful water-insolublepolymers include, but are not limited to, ethyl cellulose, hydroxypropylethyl cellulose, cellulose acetate phthalate, hydroxypropyl methylcellulose phthalate and combinations thereof. For higher dosages, it maybe desirable to incorporate a polymer which provides a high level ofviscosity as compared to polymers suitable for lower dosages.

As used herein the phrase “water-soluble polymer” and variants thereofrefer to a polymer that is at least partially soluble in water, anddesirably fully or predominantly soluble in water, or absorbs water.Polymers that absorb water are often referred to as beingwater-swellable polymers. The materials useful with the presentinvention may be water-soluble or water-swellable at room temperatureand other temperatures, such as temperatures exceeding room temperature.Moreover, the materials may be water-soluble or water-swellable atpressures less than atmospheric pressure. Desirably, the water-solublepolymers are water-soluble or water-swellable having at least 20 percentby weight water uptake. Water-swellable polymers having a 25 or greaterpercent by weight water uptake are also useful. In some embodiments,films formed from such water-soluble polymers may be sufficientlywater-soluble to be dissolvable upon contact with bodily fluids.

Other polymers useful for incorporation into the films includebiodegradable polymers, copolymers, block polymers and combinationsthereof. It is understood that the term “biodegradable” is intended toinclude materials that chemically degrade in the presence of a solvent,as opposed to materials that physically break apart (i.e., bioerodablematerials). Among the known useful polymers or polymer classes whichmeet the above criteria are: poly(glycolic acid) (PGA), poly(lacticacid) (PLA), polydioxanes, polyoxalates, poly(α-esters), polyanhydrides,polyacetates, polycaprolactones, poly(orthoesters), polyamino acids,polyaminocarbonates, polyurethanes, polycarbonates, polyamides,poly(alkyl cyanoacrylates), and mixtures and copolymers thereof.Additional useful polymers include, stereopolymers of L- and D-lacticacid, copolymers of bis(p-carboxyphenoxy) propane acid and sebacic acid,sebacic acid copolymers, copolymers of caprolactone, poly(lacticacid)/poly(glycolic acid)/polyethyleneglycol copolymers, copolymers ofpolyurethane and (poly(lactic acid), copolymers of polyurethane andpoly(lactic acid), copolymers of α-amino acids, copolymers of α-aminoacids and caproic acid, copolymers of α-benzyl glutamate andpolyethylene glycol, copolymers of succinate and poly(glycols),polyphosphazene, polyhydroxy-alkanoates and mixtures thereof. Binary andternary systems are contemplated.

Other specific polymers useful include those marketed under the Medisorband Biodel trademarks. The Medisorb materials are marketed by the DupontCompany of Wilmington, Del. and are generically identified as a“lactide/glycolide copolymer” containing “propanoic acid,2-hydroxy-polymer with hydroxy-polymer with hydroxyacetic acid.” Foursuch polymers include lactide/glycolide 100L, believed to be 100%lactide having a melting point within the range of 338°−347° F.(170°-175° C.); lactide/glycolide 100L, believed to be 100% glycolidehaving a melting point within the range of 437°−455° F. (225°−235° C.);lactide/glycolide 85/15, believed to be 85% lactide and 15% glycolidewith a melting point within the range of 338°−347° F. (170°-175° C.);and lactide/glycolide 50/50, believed to be a copolymer of 50% lactideand 50% glycolide with a melting point within the range of 338°−347° F.(170°−175° C.).

The Biodel materials represent a family of various polyanhydrides whichdiffer chemically.

Although a variety of different polymers may be used, it is desired toselect polymers that provide mucoadhesive properties to the film, aswell as a desired dissolution and/or disintegration rate. In particular,the time period for which it is desired to maintain the film in contactwith the mucosal tissue depends on the type of active contained in thecomposition. Some actives may only require a few minutes for deliverythrough the mucosal tissue, whereas other actives may require up toseveral hours or even longer. Accordingly, in some embodiments, one ormore water-soluble polymers, as described above, may be used to form thefilm. In other embodiments, however, it may be desirable to usecombinations of water-soluble polymers and polymers that arewater-swellable, water-insoluble and/or biodegradable, as providedabove. The inclusion of one or more polymers that are water-swellable,water-insoluble and/or biodegradable may provide films with slowerdissolution or disintegration rates than films formed from water-solublepolymers alone. As such, the film may adhere to the mucosal tissue forlonger periods or time, such as up to several hours, which may bedesirable for delivery of certain active components.

Desirably, the individual film dosage has a small size that is betweenabout 0.5-1 inch by about 0.5-1 inch. Most preferably, the film dosageis about 0.75 inches×0.5 inches. The film dosage should have goodadhesion when placed in the buccal cavity or in the sublingual region ofthe user. Further, the film dosage should disperse and dissolve at amoderate rate, that is, between about 1 minute to about 30 minutes, andmost desirably between about 10 minutes and about 20 minutes. In someembodiments, however, it may be desired to allow the individual filmdosage to dissolve slower, over a period of longer than about 30minutes. In such slow dissolving embodiments, it is preferable that thefilm dosage has strong mucoadhesion properties. In other embodiments,however, it may be desirable to use a faster dissolving material, forexample between about 1 to about 3 minutes. Further, the film dosageshould include components that aid in adhesion to the inner surface ofthe user's oral cavity, such as the buccal cavity or sublingually. Inparticular, for dual-layered films, the region including the agonistshould have a higher degree of adhesion than the region including theantagonist. In this fashion, the agonist may be released quicker andingested by the user.

For instance, in some embodiments, the films may include polyethyleneoxide alone or in combination with a second polymer component. In someembodiments, the films may include polymers other than polyethyleneoxide. The second polymer may be another water-soluble polymer, awater-swellable polymer, a water-insoluble polymer, a biodegradablepolymer or any combination thereof. Suitable water-soluble polymersinclude, without limitation, any of those provided above. In someembodiments, the water-soluble polymer may include hydrophiliccellulosic polymers, such as hydroxypropyl cellulose and/orhydroxypropylmethyl cellulose. Other specific examples of useful watersoluble polymers include, but are not limited to, polyethylene oxide(PEO), pullulan, hydroxypropyl cellulose, polydextrose, polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodiumalginate, propylene glycol alginate, carrageenan, polyethylene glycol,xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum,polyacrylic acid, methylmethacrylate copolymer, poloxamer polymers,copolymers of acrylic acid and alkyl acrylate (available as Pemulen®polymers), carboxyvinyl copolymers, starch, gelatin, pectin, andcombinations thereof.

Specific examples of useful water insoluble polymers include, but arenot limited to, ethyl cellulose, hydroxypropyl ethyl cellulose,cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate,acrylic polymers, vinyl acetate, sodium sulphonated polyesters,carboxylated acrylics, trimethylpentanediol/adipic acid/glycerin crosspolymer, polyglycerol-2-diisostearate/IPDI copolymer, carboxylated vinylacetate copolymer, vinylpyrrolicone/vinyl acetate/alkylaminoacrylateterpolymers, vinylpyrrolidone/vinyl acetate copolymer, and combinationsthereof.

In accordance with some embodiments, polyethylene oxide may range fromabout 20% to 100% by weight in the polymer component, more specificallyabout 30% to about 70% by weight, and even more specifically about 40%to about 60% by weight. In some embodiments, one or morewater-swellable, water-insoluble and/or biodegradable polymers also maybe included in the polyethylene oxide-based film. Any of thewater-swellable, water-insoluble or biodegradable polymers providedabove may be employed. The second polymer component may be employed inamounts of about 0% to about 80% by weight in the polymer component,more specifically about 30% to about 70% by weight, and even morespecifically about 40% to about 60% by weight.

The molecular weight of the polyethylene oxide also may be varied. Insome embodiments, high molecular weight polyethylene oxide, such asabout 4 million, may be desired to increase mucoadhesivity of the film.In some other embodiments, the molecular weight may range from about100,000 to 900,000, more specifically from about 100,000 to 600,000, andeven more specifically from about 100,000 to 300,000. In someembodiments, it may be desirable to combine high molecular weight(600,000 to 900,000) with low molecular weight (100,000 to 300,000)polyethylene oxide in the polymer component. Suitable polymers includethose described in the applicant's co-pending application, U.S.Publication Number 2008-0260809, the entire contents of which areincorporated by reference herein.

A variety of optional components and fillers also may be added to thefilms. These may include, without limitation: surfactants; plasticizers;polyalcohols; anti-foaming agents, such as silicone-containingcompounds, which promote a smoother film surface by releasing oxygenfrom the film; thermo-setting gels such as pectin, carageenan, andgelatin, which help in maintaining the dispersion of components;inclusion compounds, such as cyclodextrins and caged molecules; coloringagents; and flavors. In some embodiments, more than one active componentmay be included in the film.

Chelators may be included in the films. Applicants have surprisinglydiscovered that chelators may be employed to reduce or eliminate theoxidation of active ingredients in film compositions. In fact, chelatorscan be as effective as or even more effective than anti-oxidants inpreventing or reducing oxidation of some actives, such as naloxone.

In practice, a chelator is added to the compositions of the presentinvention in the same manner as any other additive. In certainembodiments, a chelator is added to one or more regions of amulti-region film. In another embodiment, a chelator is added to one orboth regions of a dual region film. In these embodiments, the chelatormay be the same in each region or may differ between regions.

The chelator may be any chelator known in the art. Chelators have twofunctional groups that donate a pair of electrons such as ═O, —NH2,—COO— and allow ring formation with metal. Examples of chelatorsinclude, for example, ethylenediaminetetraacetic acid (EDTA), proteins,polysaccharides, polynucleic acids, glutamic acid, histidine, organicdiacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humicacid, phosphonates, transferrin, desferrioxamine, and combinationsthereof. Preferably, the chelator is EDTA or a salt thereof. Salts ofEDTA include, for example, EDTA disodium salt, EDTA tetraammonium salt,EDTA tetrasodium salt, EDTA calcium disodium salt, EDTA tetrapotassiumsalt, EDTA diammonium salt.

In an embodiment of the present invention, the chelator is present inthe film dosage compositions in an amount of about 0.1 to about 10% byweight of the total film dosage composition, preferably in an amount of0.5 to about 7.5%, and more preferable in an amount of about 1 to about2%.

In an embodiment of the present invention, the weight ratio ofantagonist, such as naloxone, to chelator of about 0.2 to 2 to about 2to 0.5, preferably in a weight ratio of 1 to 2 about 2 to 1.

Antioxidants may be included in the films. Antioxidants may be includedin the films. Examples of such antioxidants include phenol antioxidantssuch as dibutylhydroxytoluene (BHT) IUPAC name:2,6-bis(1,1-dimethylethyl)-4-methylphenol) and dibutylatedhydroxyanisole (BHA); propyl gallate, sodium sulfate, citric acid,sodium metabusulfite, ascorbic acid, tocopherol, tocopherol esterderivatives, 2-mercaptobenzimidazole and the like. Among theseantioxidants, preferred are ascorbic acid, dibutylhydroxytoluene (BHT),propyl gallate, sodium sulfite, citric acid, sodium metabisulfite, andcombinations thereof. The amount of an antioxidant to be used ispreferably 0.1 to 20% by mass and more preferably 0.5 to 10% by mass perthe total mass of the film dosage composition.

In an embodiment of the present invention, the film dosage compositioneither a chelator or an antioxidant. In another embodiment, the filmdosage composition includes both a chelator and an antioxidant.

Additives may be included in the films. Examples of classes of additivesinclude excipients, lubricants, buffering agents, stabilizers, blowingagents, pigments, coloring agents, fillers, bulking agents, sweeteningagents, flavoring agents, fragrances, release modifiers, adjuvants,plasticizers, flow accelerators, mold release agents, polyols,granulating agents, diluents, binders, buffers, absorbents, glidants,adhesives, anti-adherents, acidulants, softeners, resins, demulcents,solvents, surfactants, emulsifiers, elastomers and mixtures thereof.These additives may be added with the active ingredient(s).

Useful additives include, for example, gelatin, vegetable proteins suchas sunflower protein, soybean proteins, cotton seed proteins, peanutproteins, grape seed proteins, whey proteins, whey protein isolates,blood proteins, egg proteins, acrylated proteins, water-solublepolysaccharides such as alginates, carrageenans, guar gum, agar-agar,xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gumkaraya, gum tragancanth), pectin, water-soluble derivatives ofcellulose: alkylcelluloses hydroxyalkylcelluloses andhydroxyalkylalkylcelluloses, such as methylcelulose,hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,hydroxyethylmethylcellulose, hydroxypropylmethylcellulose,hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcelluloseesters such as cellulose acetate phthalate (CAP),hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses,carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such ascarboxymethylcellulose and their alkali metal salts; water-solublesynthetic polymers such as polyacrylic acids and polyacrylic acidesters, polymethacrylic acids and polymethacrylic acid esters,polyvinylacetates, polyvinylalcohols, polyvinylacetatephthalates (PVAP),polyvinylpyrrolidone (PVP), PVY/vinyl acetate copolymer, andpolycrotonic acids; also suitable are phthalated gelatin, gelatinsuccinate, crosslinked gelatin, shellac, water-soluble chemicalderivatives of starch, cationically modified acrylates and methacrylatespossessing, for example, a tertiary or quaternary amino group, such asthe diethylaminoethyl group, which may be quaternized if desired; andother similar polymers.

Such extenders may optionally be added in any desired amount desirablywithin the range of up to about 80%, desirably about 3% to 50% and moredesirably within the range of 3% to 20% based on the weight of all filmcomponents.

Further additives may be flow agents and opacifiers, such as the oxidesof magnesium aluminum, silicon, titanium, etc. desirably in aconcentration range of about 0.02% to about 3% by weight and desirablyabout 0.02% to about 1% based on the weight of all film components.

Further examples of additives are plasticizers which includepolyalkylene oxides, such as polyethylene glycols, polypropyleneglycols, polyethylene-propylene glycols, organic plasticizers with lowmolecular weights, such as glycerol, glycerol monoacetate, diacetate ortriacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol,sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributylcitrate, and the like, added in concentrations ranging from about 0.5%to about 30%, and desirably ranging from about 0.5% to about 20% basedon the weight of the polymer.

There may further be added compounds to improve the texture propertiesof the starch material such as animal or vegetable fats, desirably intheir hydrogenated form, especially those which are solid at roomtemperature. These fats desirably have a melting point of 50° C. orhigher. Preferred are tri-glycerides with C₁₂-, C₁₄-, C₁₆-, C₁₈-, C₂₀-and C₂₂-fatty acids. These fats can be added alone without addingextenders or plasticizers and can be advantageously added alone ortogether with mono- and/or di-glycerides or phosphatides, especiallylecithin. The mono- and di-glycerides are desirably derived from thetypes of fats described above, i.e. with C₁₂-, C₁₄-, C₁₆-, C₁₈-, C₂₀-and C₂₂-fatty acids.

The total amounts used of the fats, mono-, di-glycerides and/orlecithins may be up to about 5% and preferably within the range of about0.5% to about 2% by weight of the total film composition.

It further may be useful to add silicon dioxide, calcium silicate, ortitanium dioxide in a concentration of about 0.02% to about 1% by weightof the total composition. These compounds act as flow agents andopacifiers.

Lecithin is one surface active agent for use in the films describedherein. Lecithin may be included in the feedstock in an amount of fromabout 0.25% to about 2.00% by weight. Other surface active agents, i.e.surfactants, include, but are not limited to, cetyl alcohol, sodiumlauryl sulfate, the Spans™ and Tweens™ which are commercially availablefrom ICI Americas, Inc. Ethoxylated oils, including ethoxylated castoroils, such as Cremophor® EL which is commercially available from BASF,are also useful. Carbowax™ is yet another modifier which is very usefulin the present invention. Tweens™ or combinations of surface activeagents may be used to achieve the desired hydrophilic-lipophilic balance(“HLB”).

Other ingredients include binders which contribute to the ease offormation and general quality of the films. Non-limiting examples ofbinders include starches, pregelatinize starches, gelatin,polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose,ethylcellulose, polyacrylamides, polyvinyloxoazolidone, andpolyvinylalcohols. If desired, the film may include other additives,such as keratin, or proteins, including proteins that are useful informing a gel, such as gelatine.

Further potential additives include solubility enhancing agents, such assubstances that form inclusion compounds with active components. Suchagents may be useful in improving the properties of very insolubleand/or unstable actives. In general, these substances aredoughnut-shaped molecules with hydrophobic internal cavities andhydrophilic exteriors. Insoluble and/or instable actives may fit withinthe hydrophobic cavity, thereby producing an inclusion complex, which issoluble in water. Accordingly, the formation of the inclusion complexpermits very insoluble and/or instable actives to be dissolved in water.A particularly desirable example of such agents are cyclodextrins, whichare cyclic carbohydrates derived from starch. Other similar substances,however, are considered well within the scope of the present invention.

Suitable coloring agents include food, drug and cosmetic colors (FD&C),drug and cosmetic colors (D&C), or external drug and cosmetic colors(Ext. D&C). These colors are dyes, their corresponding lakes, andcertain natural and derived colorants. Lakes are dyes absorbed onaluminum hydroxide.

Other examples of coloring agents include known azo dyes, organic orinorganic pigments, or coloring agents of natural origin. Inorganicpigments are preferred, such as the oxides or iron or titanium, theseoxides, being added in concentrations ranging from about 0.001 to about10%, and preferably about 0.5 to about 3%, based on the weight of allthe components.

Flavors may be chosen from natural and synthetic flavoring liquids. Anillustrative list of such agents includes volatile oils, syntheticflavor oils, flavoring aromatics, oils, liquids, oleoresins or extractsderived from plants, leaves, flowers, fruits, stems and combinationsthereof. A non-limiting representative list of examples includes mintoils, cocoa, and citrus oils such as lemon, orange, grape, lime andgrapefruit and fruit essences including apple, pear, peach, grape,strawberry, raspberry, cherry, plum, pineapple, apricot or other fruitflavors.

Other useful flavorings include aldehydes and esters such asbenzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime),neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon),aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehydeC-12 (citrus fruits), tolyl aldehyde (cherry, almond),2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin),combinations thereof and the like.

The sweeteners may be chosen from the following non-limiting list:glucose (corn syrup), dextrose, invert sugar, fructose, and combinationsthereof; saccharin and its various salts such as the sodium salt;dipeptide sweeteners such as aspartame; dihydrochalcone compounds,glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives ofsucrose such as sucralose; sugar alcohols such as sorbitol, mannitol,xylitol, and the like. Also contemplated are hydrogenated starchhydrolysates and the synthetic sweetener3,6-dihydro-6-methyl-1-1-1,2,3-oxathiazin-4-one-2,2-dioxide,particularly the potassium salt (acesulfame-K), and sodium and calciumsalts thereof, and natural intensive sweeteners, such as Lo Han Kuo.Other sweeteners may also be used.

The films may include one or more additives to provide a taste maskingof the active component. For example, the films may include ionicexchange resins, including but not limited to a water-insoluble organicor inorganic matrix material having covalently bound functional groupsthat are ionic or capable of being ionized under appropriate conditions.The organic matrix may be synthetic (e.g., polymers or copolymers oracrylic acid, methacrylic acid, sulfonated styrene or sulfonateddivinylbenzene) or partially synthetic (e.g., modified cellulose ordextrans). The inorganic matrix may be, for example, silica gel modifiedby the addition of ionic groups. Most ion exchange resins arecross-linked by a crosslinking agent, such as divinylbenzene.

Anti-foaming and/or de-foaming components may also be used with thefilms. These components aid in the removal of air, such as entrappedair, from the film-forming compositions. Such entrapped air may lead tonon-uniform films. Simethicone is one particularly useful anti-foamingand/or de-foaming agent. The present invention, however, is not solimited and other anti-foam and/or de-foaming agents may suitable beused.

As a related matter, simethicone and related agents may be employed fordensification purposes. More specifically, such agents may facilitatethe removal of voids, air, moisture, and similar undesired components,thereby providing denser, and thus more uniform films. Agents orcomponents which perform this function can be referred to asdensification or densifying agents. As described above, entrapped air orundesired components may lead to non-uniform films.

Simethicone is generally used in the medical field as a treatment forgas or colic in babies. Simethicone is a mixture of fully methylatedlinear siloxane polymers containing repeating units ofpolydimethylsiloxane which is stabilized with trimethylsiloxyend-blocking unites, and silicon dioxide. It usually contains 90.5-99%polymethylsiloxane and 4-7% silicon dioxide. The mixture is a gray,translucent, viscous fluid which is insoluble in water.

When dispersed in water, simethicone will spread across the surface,forming a thin film of low surface tension. In this way, simethiconereduces the surface tension of bubbles air located in the solution, suchas foam bubbles, causing their collapse. The function of simethiconemimics the dual action of oil and alcohol in water. For example, in anoily solution any trapped air bubbles will ascend to the surface anddissipate more quickly and easily, because an oily liquid has a lighterdensity compared to a water solution. On the other hand, analcohol/water mixture is known to lower water density as well as lowerthe water's surface tension. So, any air bubbles trapped inside thismixture solution will also be easily dissipated. Simethicone solutionprovides both of these advantages. It lowers the surface energy of anyair bubbles that trapped inside the aqueous solution, as well aslowering the surface tension of the aqueous solution. As the result ofthis unique functionality, simethicone has an excellent anti-foamingproperty that can be used for physiological processes (anti-gas instomach) as well as any for external processes that require the removalof air bubbles from a product.

In order to prevent the formation of air bubbles in the films, themixing step may be performed under vacuum. However, as soon as themixing step is completed, and the film solution is returned to thenormal atmosphere condition, air will be re-introduced into or contactedwith the mixture. In many cases, tiny air bubbles will be again trappedinside this polymeric viscous solution. The incorporation of simethiconeinto the film-forming composition either substantially reduces oreliminates the formation of air bubbles during and after mixing.

Simethicone may be added to the film-forming mixture as an anti-foamingagent in an amount from about 0.01 weight percent to about 5.0 weightpercent, more desirably from about 0.05 weight percent to about 2.5weight percent, and most desirably from about 0.1 weight percent toabout 1.0 weight percent.

Any other optional components described in commonly assigned U.S. Pat.No. 7,425,292 and U.S. application Ser. No. 10/856,176, referred toabove, also may be included in the films described herein.

When the dosage form includes at least one antagonist in addition to theagonist, it may be desired to control the release of the antagonist, soas to minimize or wholly prevent the absorption of the antagonist fromthe dosage form when taken orally. In this fashion, the antagonist maybe released faster and a larger proportion of it may be present as theionized form in solution, thereby lessening the likelihood of itsabsorption in the body. Desirably, the dosage form is a self-supportingfilm composition, which is placed into the oral cavity of the user. In adosage form that is to be placed in the oral cavity, it is desired toabsorb the agonist buccally, so as to provide rapid absorption of theagonist into the body of the user. At the same time, it may be desiredto inhibit or reduce absorption of any antagonist buccally, therebyallowing the antagonist to be swallowed and destroyed in the stomach, orin some cases absorbed in the colon. Inhibiting the absorption of anantagonist may alternatively be achieved via physical means, such as byencapsulating the antagonist in a material that blocks absorption. It isdesired, however, to reduce the absorption of the antagonist by chemicalmeans, such as by controlling the local pH of the dosage form.

It has been found that by controlling the local pH of the dosage form,the release and/or absorption of the actives therein may be controlled.For example, in a dosage that includes an amount of an agonist, thelocal pH may be controlled to a level that optimizes its release and/orabsorption into the oral cavity of the user. In dosages incorporating anamount of an agonist and an amount of an antagonist, the local pH may becontrolled to a level that maximizes the release and/or oral absorptionof the agonist while simultaneously minimizing the release and/or oralabsorption of the antagonist. For example, the film dosage may includedistinct regions, one region including an agonist and the other regionincluding an antagonist, where the local pH of each region is optimizedfor the desired effect.

The dosage form preferably includes a combination of an agonist and anantagonist, while the dosage has a controlled local pH. It should beunderstood that the present invention is not limited to the use of anyone particular agonist and/or antagonist, and any agonist (or partialagonist) and any antagonist may be incorporated into the presentinvention. The agonist and optional antagonist should be selected fromthose agonists and antagonists that are useful in treating theparticular symptom being treated. The inventive films discussed hereinare best suited for agonists and/or antagonists that are basic innature. Suitable agonists (and/or partial agonists) may includebuprenorphine (pKa=8.42), sufentanil (pKa=8.0), morphine (pKa=8.0),fentanil (pKa=8.4), alfentanil (pKa=6.5), pethidine (pKa=8.7),apomorphine (pKa=8.9), alphaprodine (pKa=8.7), remifentanil (pKa=7.0),methadone (pKa=9.2), codeine (pKa=8.2), dihydrocodeine (pKa=9.4),morphine (pKa=8.0), oxycodone (pKa=8.53), oxymorphone (pKa=8.17),tramadol (pKa=9.41), or pharmaceutically acceptable salts thereof.Suitable antagonists (and/or partial antagonists) may include naloxone,naltrexone, nalorphine and levallorphan, or therapeutically acceptablesalts thereof.

As discussed above, the local pH of the dosage is preferably controlledto provide the desired release and/or absorption of the agonist andantagonist. Suitable agonists may have a pKa of about 5 to about 9.5,and most preferably from about 8.0 to about 9.0. Suitable antagonistsmay have a pKa of about 6.0 to about 9.0, and most preferably about 7.0to about 9.0. For example, naloxone has a pKa of about 7.94.

According to pH partition theory, one would expect that saliva (whichhas a local pH of about 6.5) would maximize the absorption of bothactives. As generally understood, absorption of an active depends on theavailable unionized form of the active. Thus, as the local pH of thesurrounding environment is lowered, basic actives will be more ionized,and less will be available for absorption. For an active which has a pKaof about 8, one would expect a higher level of absorption to occur at alocal pH level of about 6.5, whereas a lower level of absorption shouldoccur at a local pH of about 3.5, since most of the active would beionized. As will be described in more detail in the Examples below,controlling the local pH of the film compositions of the presentinvention provides a system in which the desired release and/orabsorption of the components is achieved.

In one embodiment, the dosage form is a self-supporting film. In thisembodiment, the film dosage includes a polymer carrier matrix, atherapeutically effective amount of an agonist or a pharmaceuticallyacceptable salt thereof, and a buffer. Preferably, the agonist is apartial agonist, and most desirably the agonist is an opioid agonist,such as buprenorphine. The buffer is preferably capable of providing alocal pH of the composition within a range that provides a controllablelevel and desirably an optimal treatment level of absorption of theagonist. For example, it may be desired to provide an absorption ofbuprenorphine that is bioequivalent to a Suboxone® tablet.

It has been surprisingly discovered by the Applicants that certainagonists, such as buprenorphine, are capable of being suitably absorbedwhen the local pH of the film composition is either between about 3 toabout 4 or between about 5 to about 9. Thus, the local pH for the filmincluding the agonist may be either from about 3 to about 4 or fromabout 5 to about 9. To provide a maximum absorption of buprenorphine,for example, the local pH of the film composition may be about 5.5. Toprovide an absorption of buprenorphine that is bioequivalent to theSuboxone® tablet, the local pH of the film composition may be about 6 toabout 7. The resulting dosage is a film composition that allows for arapid and effective release of the agonist (such as buprenorphine) intothe oral cavity of the user. At the same time, the film compositiondesirably has a sufficient adhesion profile, such that the film cannoteasily be removed, or cannot be removed at all, from the oral cavity ofthe user once it has been placed into the cavity. Full release of theagonist may take place within less than about thirty minutes, e.g.,within about 10 minutes to about 30 minutes and preferably remains inthe oral cavity for at least 1 minute and desirably about 1 to about 30minutes.

It may be desirable to combine the opioid agonist (or partial agonist)in the film composition with an opioid antagonist or a pharmaceuticallyacceptable salt thereof. The agonist and antagonist may be dispersedthroughout the dosage separately or the agonist and antagonist may beseparately dispersed in individual film regions. Most desirably theantagonist includes naloxone, but any suitable antagonist may beselected as desired. The antagonist may optionally be water-soluble, soas to render separation of the antagonist and agonist difficult, therebylessening the potential for diversion abuse of the agonist.

As with a film including an agonist, a film including an agonist and anantagonist is desirably pH-controlled through the inclusion of a buffer.At the desired local pH level of the agonist and the antagonist, optimalabsorption of the agonist may be achieved while the absorption of theantagonist may be greatly inhibited.

The film may contain any desired level of self-supporting film formingpolymer, such that a self-supporting film composition is provided. Inone embodiment, the film composition contains a film forming polymer inan amount of at least 25% by weight of the composition. The film formingpolymer may alternatively be present in an amount of at least 50% byweight of the composition, and desirably in a range of about 25% toabout 75%, and most desirably from about 30% to about 50% by weight ofthe composition. As explained above, any film forming polymers may beused as desired.

Any desired level of agonist and optional antagonist may be included inthe dosage, so as to provide the desired therapeutic effect. In oneparticular embodiment, the film composition includes about 2 mg to about16 mg of agonist per dosage. More desirably, the film compositionincludes about 4 mg to about 12 mg of agonist per dosage. If desired,the film composition may include about 0.5 mg to about 5 mg ofantagonist per dosage. More desirably, the film composition includesabout 1 mg to about 3 mg of antagonist per dosage. If an antagonist isincorporated into the film, the film composition may include theantagonist in a ratio of about 6:1-2:1 agonist to antagonist. Mostdesirably, the film composition contains about 4:1 agonist to antagonistper dosage. For example, in one embodiment, the dosage includes anagonist in an amount of about 12 mg, and includes an antagonist in anamount of about 3 mg.

The film compositions further desirably include at least one buffer soas to control the local pH of the film composition. Any desired level ofbuffer may be incorporated into the film composition so as to providethe desired local pH level. The buffer is preferably provided in anamount sufficient to control the release from the film and/or theabsorption into the body of the agonist and the optional antagonist. Ina desired embodiment, the film composition includes buffer in a ratio ofbuffer to agonist in an amount of from about 2:1 to about 1:5(buffer:agonist). The buffer may alternatively be provided in a 1:1ratio of buffer to agonist. A film composition including an antagonistpreferably has a local pH of about 2 to about 4. Any buffer may be usedas desired. In some embodiments, the buffer may include sodium citrate,citric acid, succinic acid, malic acid, phosphoric acid, boric acid, andcombinations thereof. The buffer may include a buffering systemincluding a combination of components, such as Citric Acid/SodiumCitrate, Succinic Acid/Monosodium Succinate, Glycine/SodiumGlycine,Malic Acid/Sodium Malate, Phosphoric Acid/Sodium Phosphate, FumaricAcid/Sodium Fumarate, Monosodium Phosphate/Disodium Phosphate, and BoricAcid/Sodium Borate.

In this embodiment, the resulting film composition includes a polymermatrix, an agonist, and an optional antagonist, while the filmcomposition has a controlled local pH to the level desired. The bufferis desirably present in an amount to provide a therapeutically adequateabsorption of the agonist, while simultaneously limiting or preventingsubstantial absorption of the antagonist. Controlling of the local pHallows for the desired release and/or absorption of the components, andthus provides a more useful and effective dosage.

The film dosage composition may include a polymer carrier matrix, atherapeutically effective amount of agonist, a therapeutically effectiveamount of antagonist, and a buffering system. A “therapeuticallyeffective amount” of an antagonist is intended to refer to an amount ofthe antagonist that is useful in diverting abuse of the agonist by auser. The buffering system may include a buffer in addition to asolvent. The buffering system desirably includes a sufficient level ofbuffer so as to provide a desired local pH level of the film dosagecomposition.

In addition to a desired local pH level, the buffer desirably has abuffer capacity sufficient to maintain ionization of the optionalantagonist during the time that the composition is in the oral cavity ofa user. Maintaining ionization of the antagonist serves to limit theabsorption of the antagonist, and thus provide the desired control ofthe antagonist. While the ionization of the antagonist is limited, theionization of the agonist may not be so limited. As such, the resultingdosage form provides absorption of the agonist to the user, whilesufficiently reducing and/or preventing absorption of the antagonist.

In other embodiments, the film dosage composition of the presentinvention may include an agonist in a sufficient amount so as to providea release profile bioequivalent to a tablet containing a higher amountof the agonist. By providing a film dosage composition with an agonistand simultaneously controlling the local pH of the film dosagecomposition, an effective release and absorption of the agonist may beachieved with less of the agonist present in the dosage. For example,the film dosage composition may include an agonist in an amount that isat least 1.5 times less than the amount of the agonist required in atablet, but still provides a bioequivalent release profile. In someembodiments, the agonist may be a partial agonist. In some embodimentsthe agonist may be an opioid agonist. In desired embodiments, theagonist includes buprenorphine or a pharmaceutically acceptable saltthereof.

The film dosage composition including an agonist, may be configured toprovide an in vivo plasma profile having a mean maximum plasmaconcentration (Cmax) in a desired range. For example, the desired Cmaxmay be a bioequivalent level to that of a Suboxone® tablet. It has beendiscovered by the Applicants that controlling the Cmax of the filmcomposition allows one to control the absorption of the active (such asan agonist) into the user. The resulting film composition is moreeffective and suitable for delivery to a user.

In one embodiment, the Cmax of the film composition may be about 6.4ng/ml or less. If desired, the Cmax of the film composition may be lessthan about 5.2 ng/ml, less than about 3.8 ng/ml, less than about 1.9ng/ml, or less than about 1.1 ng/ml, depending on the desired dosagelevel. In such embodiments, the agonist may be present in an amount offrom about 2 mg to about 16 mg per dosage, or, if desired about 4 mg toabout 12 mg per dosage. The agonist may include buprenorphine or apharmaceutically acceptable salt thereof.

It has further been discovered that, by controlling the mean area underthe curve (AUC) value of the film composition, a more effective dosageform may be provided. In one embodiment, the film composition mayinclude a mean AUC value of about 6.8 hr·ng/ml or greater.Alternatively, the film composition may include a mean AUCinf value offrom about 6.8 hr·ng/ml to about 66 hr·ng/ml.

As explained above, the film compositions may include an optionalantagonist. When the film composition includes a combination of agonistand antagonist, the film composition may be configured to provide aparticular Cmax and/or AUC for the antagonist. For example, when abuprenorphine agonist and a naloxone antagonist are incorporated intothe film composition, the naloxone may be configured to provide a Cmaxof less than about 400 pg/ml, less than about 318 pg/ml, less than about235 pg/ml, less than about 92 pg/ml or less than about 64 pg/ml. In suchfilms, the naloxone may provide a mean AUC value of less than about 1030hr·ng/ml.

In formulations which include an agonist in combination with anantagonist, the film composition may be prepared to provide a desiredCmax and/or AUC value for each of the agonist and antagonist. Forexample, a dosage having 16 mg of agonist and 4 mg of antagonist mayprovide an in vivo plasma profile having a Cmax of less than about 6.4ng/ml for the agonist and an in vivo plasma profile having a Cmax ofless than about 400 pg/ml for the antagonist. Such formulation may alsoprovide an AUC value of more than about 6.8 hr·ng/ml for the agonist. Ifdesired, the formulation may provide an AUCinf value of less than about1030 hr·pg/ml for the antagonist. Bioequivalence levels are set forth inmore detail in the Examples discussed below. Such compositions mayinclude the agonist and the antagonist in any desired amount, and in apreferred embodiment, the composition includes about 2 mg to about 16 mgof the agonist per dosage and about 0.5 mg to about 4 mg of theantagonist per dosage. Most desirably, the agonist and antagonist arepresent in amounts of about 4:1 by weight agonist to antagonist.

In one particular embodiment, there may be provided a self-supportingfilm dosage composition including more than one region (referred to as a“dual-film product” or a “dual-region product”). The multiple regionsmay be disposed on top of each other, to the side of each other, ordisposed internally of each other. For example, the dosage compositionmay include two separate regions, disposed in such a configuration wherethe first region is on top of the second region, or vice versa. Ifdesired, the two regions may be laminated to each other so as to providea single dosage form. In such embodiments, the first region may be driedprior to laminating any additional regions thereto. Similarly, thesecond region may be dried prior to laminating the first region thereto.Alternatively, either the first or second region may be at leastpartially dried prior to laminating any additional regions thereto.

In such multi-region embodiments, there is provided a first region,which includes a first polymeric matrix and a therapeutically effectiveamount of an agonist. The agonist may be a partial agonist, and theagonist may be an opioid agonist. One such opioid agonist includesbuprenorphine, but any desired agonist may be used to treat theparticular symptom desired. The first region desirably includes a firstbuffering system in an amount sufficient to provide a local pH of theagonist so as to optimize the release and/or absorption of the agonist.The first region may be in communication with a second region. Thesecond region may include a second polymeric matrix and atherapeutically effective amount of an antagonist. One such antagonistincludes naloxone, but any desired antagonist may be used as desired.The second region may further include a second buffering system in anamount sufficient to provide a local pH of the antagonist so as toinhibit the absorption of the antagonist. In some embodiments, it may bedesirable to have one region be dissolved at a faster rate than thesecond region when it is placed into the mouth of the user. For example,it may be desired to have the region including an antagonist dissolve ata faster rate than the region including an agonist, or vice versa.

In such multi-region film dosages, the first and second regions may workin cooperation to provide a desired absorption profile of the agonistand the antagonist. For example, the first buffering system may bepresent in an amount sufficient to provide increased absorption of theagonist, while the second buffering system is present in an amountsufficient to provide a decreased absorption of the antagonist. In someembodiments, the first buffering system may be present in an amountsufficient to provide a local pH of the first region so as to provide anoptimum absorption of the agonist, i.e., of from either about 3 to about4 or of from about 4 to about 9, and more specifically from about 6 toabout 9. In some embodiments, the second buffering system may be presentin an amount sufficient to provide a local pH of the second region offrom about 2 to about 4, and more specifically about 2 to about 3. For amulti-region film dosage including buprenorphine in the first region andnaloxone in the second region, the local pH of the buprenorphine regionis desirably either from about 3 to about 4 or from about 5.5 to about6.5, and the local pH of the naloxone region is about 2.0 to about 3.0.

Depending on the particular agonist and antagonist incorporated in thedosage, the desired local pH level for each region may be greater orlower so as to optimize absorption of the agonist while inhibitingabsorption of the antagonist. Generally, the local pH of theagonist-containing region is desirably between about 4 to about 9, andmost desirably about 6 to about 9. The local pH for theantagonist-containing region is most desirably about 2 to about 4.Again, however, it will be understood that the particular agonistincorporated into the dosage may be more optimally absorbed at a higheror lower pH.

The first and second buffering systems may be the same or they may bedifferent. Additionally, the first polymeric matrix and the secondpolymeric matrix may be the same or they may be different. Any desiredlevels of agonist and antagonist may be provided, and desirably thedosage composition includes about 2 mg to about 16 mg of the agonist andabout 0.5 mg to about 4 mg of the antagonist per dosage unit. Moredesirably, the dosage composition includes about 4 mg to about 12 mg ofthe agonist and about 1 mg to about 3 mg of the antagonist per dosageunit.

The first and second regions may be formed together in any desiredmeans. In one embodiment, the second region may be coated, sprayed, orplaced onto at least one surface of the first region. Alternatively, thefirst and second regions may be co-extruded. In some embodiments, thefirst and second regions may be laminated to each other by means of asuitable composition. Further, the first region may be formed first, andthen subsequently dipped into a solution of a wet composition, which isthen allowed to dry and form the second region. As will be understood byone of ordinary skill in the art, the first region may include theantagonist while the second region includes the agonist. Further, bothregions may include a desired amount of agonist and antagonist so as toprovide a desired release and absorption.

The first region may include more components by weight than the secondregion, or vice versa. For example, the first region may have a totalweight that is more than the total weight of the second region, or viceversa. Alternatively, the first and second regions may include the sameamount of components by weight.

In another embodiment, there may be provided a self-supporting filmdosage composition having more than one region, where each regionincludes a polymeric matrix and a water-soluble and/or a water-insolubleactive. The dosage composition preferably includes a therapeuticallyeffective amount of a water-soluble active and a therapeuticallyeffective amount of water-insoluble active. Each region preferablyincludes a buffer in an amount sufficient to control the absorptionprofiles of the water-soluble and water-insoluble actives in eachregion, depending on the desired level of absorption of the activedesired. In one desired embodiment, a first buffer is present in thefirst region in an amount sufficient to obtain a local pH of one regionof about 2 to about 4, while a second buffer is present in the secondregion in an amount sufficient to obtain a local pH of the second regionof about 4 to about 9.

The present invention provides a method of treating various problems ina patient, including, for example physical pain experienced by apatient. Desirably, the patient is treated by providing a dosage to thepatient, which provides an effective release of therapeutic active butsimultaneously provides a suitable adhesion so that the dosage cannot beeasily removed. The dosage forms provided herein are particularly usefulin preventing diversion of a drug. In one method of treatment, an orallydissolvable film composition is provided to a patient.

Depending on the particular symptom sought to be treated, the filmcomposition may include one or more particular active components. In oneembodiment, the film composition includes a polymer carrier matrix and atherapeutically effective amount of an agonist. Desirably the agonist isa partial agonist. For some types of pain, the agonist may be an opioidagonist, such as buprenorphine or a pharmaceutically acceptable saltthereof. The film composition preferably includes a buffer in an amountsufficient to control the local pH of the film composition. Any bufferor buffering system may be used, including those listed above.Desirably, the local pH of the film composition including an agonist isbuffered to be about 4 to about 9, depending on the particular agonistincluded in the composition. In some embodiments, such as when theagonist is buprenorphine, the desired local pH is about 5 to about 6.5,and most desirably the local pH is about 5.5 to about 6.5. At thislevel, the absorption of the agonist may be optimized. To treat thepain, the film composition is administered to the patient, mostdesirably into the oral cavity of the patient, such as through buccalabsorption.

If desired, the composition may include a therapeutically effectiveamount of an antagonist. As explained above, the combination of anagonist and antagonist may help minimize potential abuse of the agonist.The antagonist may be any desired antagonist, and in one embodimentincludes naloxone or a pharmaceutically acceptable salt thereof. Thefilm composition is preferably administered to patient through the oralcavity of the patient, but may be administered in any desired means. Theorally dissolvable film composition is then allowed to dissolve in theoral cavity of the patient for a sufficient time so as to release theactive(s) therein. In some embodiments, the film composition may remainin the oral cavity for at least 30 seconds, and in some embodiments mayremain in the oral cavity for at least 1 minute. After the filmcomposition is placed into the oral cavity of the patient, the filmpreferably becomes sufficiently adhered so as to render its removaldifficult. After the film composition has been administered to thepatient, the active(s) are sufficiently released from the compositionand allowed to take effect on the patient.

In embodiments where there is a dual-region film composition, theadministration of the dosage may have regions of differing dissolutionrates. For example, the first region of the film composition may includean agonist and a moderate dissolving polymer. Desirably, the firstregion remains in the oral cavity for at least one minute, and up toabout 30 minutes. The second region, which may include an antagonist,desirably contains a fast dissolving polymer. As such, the second regiondissolves within less than one minute, thereby releasing the antagonistinto the body where it is ingested and ionized. In this way, theantagonist is swallowed, thereby avoiding buccal absorption. However,the antagonist is still present in the film composition beforeadministration so as to limit potential abuse of the drug should a userattempt to extract the agonist from the composition.

The film compositions of the present invention may be formed via anydesired process. Suitable processes are set forth in U.S. Pat. Nos.7,425,292 and 7,357,891, the entire contents of which are incorporatedby reference herein. In one embodiment, the film dosage composition isformed by first preparing a wet composition, the wet compositionincluding a polymeric carrier matrix, a therapeutically effective amountof an agonist, and a buffer in an amount sufficient to control the localpH of the composition to a desired level. The wet composition is castinto a film and then sufficiently dried to form a self-supporting filmcomposition. The wet composition may be cast into individual dosages, orit may be cast into a sheet, where the sheet is then cut into individualdosages. The agonist may be a partial agonist. If desired, the wetcomposition may include a therapeutically effective amount of anantagonist. In some embodiments, especially in single-region dosages,the local pH of the film may be about 2 to about 4, and moreparticularly between about 3 to about 4.

The agonist and the optional antagonist are preferably selected to treata particular problem, such as treatment of physical pain suffered by apatient. For example, the agonist may include buprenorphine or apharmaceutically acceptable salt thereof, while the antagonist mayinclude naloxone or a pharmaceutically acceptable salt thereof. The filmcomposition includes at least one buffer or buffering system so as tocontrol the local pH of the agonist and antagonist to desired levels. Inthis fashion, the absorption of the agonist may be optimized while theabsorption of the antagonist may be inhibited. In one desiredembodiment, the inventive film provides an absorption of the agonistthat is bioequivalent to that of a Suboxone® tablet.

If the desired optimum absorption of the agonist is to provide abioequivalent absorption to that of a Suboxone® tablet, the local pH ofthe film composition should provide a local pH of the agonist of eitherbetween about 3 to about 4 or between about 5.5 to about 6.5, and alocal pH of the antagonist of between about 2 to about 4. In a filmcomposition including only one region with the agonist and antagonist,the local pH is desirably about 3 to about 4 to provide a bioequivalentabsorption to the Suboxone® tablet.

Active ingredients in pharmaceutical compositions can degrade and losetheir effectiveness when included in a pharmaceutical composition andstored. In certain cases, the active ingredient may oxidize into a formthat is, for example, less bioavailable.

To minimize or prevent oxidation of the active, the film may bemanufacture in whole or in part under an inert gas environment. Apreferred inert gas is nitrogen.

Applicants have surprisingly discovered that chelators may be employedto reduce or eliminate the oxidation of active ingredients in filmcompositions. In fact, chelators are more effective than anti-oxidantsin preventing or reducing oxidation of some actives, such as naloxone.

In practice, a chelator is added to the compositions of the presentinvention in the same manner as any other additive. In certainembodiments, a chelator is added to one or more regions of amulti-region film. In another embodiment, a chelator is added to one orboth regions of a dual region film. In these embodiments, the chelatormay be the same in each region or may differ between regions.

EXAMPLES Example 1—Composition of Buprenorphine/Naloxone Films atVarious Strengths

Film strips including a combination of buprenorphine and naloxone wereprepared. Four different strength film compositions were prepared, whichinclude a ratio of buprenorphine to naloxone of 16/4, 12/3, 8/2, and2/0.5. The compositions are summarized in Table 1 below.

TABLE 1 Various Compositions of Film Dosages Buprenorphine/NaloxoneFilms Components Unit Formula (mg per film strip) Buprenorphine/Naloxone16/4 12/3 8/2 2/0.5 Ratios Active Components Buprenorphine HCl 17.2812.96 8.64 2.16 Naloxone HCl Dihydrate 4.88 3.66 2.44 0.61 InactiveComponents Polyethylene Oxide, NF 27.09 20.32 13.55 — (MW 200,000)Polyethylene Oxide, NF 12.04 9.03 6.02 19.06 (MW 100,000) PolyethyleneOxide, NF 4.82 3.62 2.41 2.05 (MW 900,000) Sugar Alcohol 12.04 9.03 6.025.87 Flavor 6.0 4.5 3.0 2.4 Citric Acid, USP 5.92 4.44 2.96 2.96 HPMC4.22 3.16 2.11 2.34 Sweetener 3.0 2.25 1.5 1.2 Sodium Citrate, anhydrous2.68 2.01 1.34 1.34 Colorant 0.03 0.02 0.01 0.01 Total (mg) 100 75 50 40

Example 2—Absorption Studies for Suboxone® Tablets

Various film and tablet products were prepared and tested for absorptiondata, including Cmax and AUC absorption levels. The products testedincluded Suboxone® tablets made with either 2 mg or 16 mg buprenorphineas well as either 0.5 mg or 4.0 mg naloxone. For 16 mg buprenorphinetablets, two 8 mg buprenorphine tablets were combined together toprovide the level of components of a 16 mg buprenorphine tablet. Ininstances where a 12 mg buprenorphine tablet was evaluated, this dosagewas obtained by combining one 8 mg buprenorphine tablet and two 2 mgbuprenorphine tablets. These products were tested for absorption levels,with the amounts listed in Table 2 below.

TABLE 2 Absorption Data for Suboxone ® products Sample C max AUCBuprenorphine (2 mg) 0.780 ng/ml 6.789 hr*ng/ml Suboxone ® TabletNaloxone (0.5 mg) 51.30 pg/ml 128.60 hr*pg/ml Suboxone ® TabletBuprenorphine (16 mg) 4.51 ng/ml 44.99 hr*ng/ml Suboxone ® TabletNaloxone (4 mg) 259.00 pg/ml 649.60 hr*pg/ml Suboxone ® Tablet

Using the data from Table 2, absorption data for the Suboxone® tabletsfor other levels of buprenorphine and naloxone are set forth in Table 2Abelow.

TABLE 2A Absorption Data for Suboxone ® tablets Sample C max AUCBuprenorphine (4 mg) 1.35 ng/ml 12.25 hr*ng/ml Suboxone ® TabletNaloxone (1 mg) 80.97 pg/ml 203 hr*pg/ml Suboxone ® Tablet Buprenorphine(8 mg) 2.29 ng/ml 23.17 hr*ng/ml Suboxone ® Tablet Naloxone (2 mg)140.31 pg/ml 351.8 hr* pg/ml Suboxone ® Tablet Buprenorphine (12 mg)3.23 ng/ml 34.08 hr*ng/ml Suboxone ® Tablet Naloxone (3 mg) 199.7 pg/ml500.6 hr*pg/ml Suboxone ® Tablet

Example 3—Evaluation of Bioequivalence of Suboxone® Tablets

Using the data generated for Suboxone® tablets in Table 2 above,acceptable bioequivalence ranges are generated so as to provide anequivalent treatment level as the Suboxone® tablet. As currentlyunderstood, a product provides a bioequivalent effect if it providesabsorption levels between about 80% to about 125% of the Suboxone®tablet. Absorption in this range is considered to be bioequivalent.

TABLE 3 Acceptable Bioequivalence Ranges for Suboxone ® Tablets (80 to125%) Description of Sample C max AUC Buprenorphine 2 mg 0.624 to 0.9755.431 to 8.486 ng/ml hr*ng/ml Naloxone 0.5 mg 41.04 to 64.13 102.88 to160.75 pg/ml hr*pg/ml Buprenorphine 16 mg 3.608 to 5.638 35.992 to56.238 ng/ml hr*ng/ml Naloxone 4 mg 207.20 to 323.75 519.68 to 812.00pg/ml hr*pg/ml

Thus, to be considered bioequivalent to the Suboxone® tablet, the Cmaxof buprenorphine is between about 0.624 and 5.638, and the AUC ofbuprenorphine is between about 5.431 to about 56.238. Similarly, to beconsidered bioequivalent to the Suboxone® tablet, the Cmax of naloxoneis between about 41.04 to about 323.75, and the AUC of naloxone isbetween about 102.88 to about 812.00.

Example 4—Composition of Buprenorphine Films at Various Strengths

Film strips including a buprenorphine were prepared. Two differentstrength film compositions were prepared, which include buprenorphine ina dosage amount of 8 mg and in a dosage amount of 2 mg. The compositionsare summarized in Table 4 below.

TABLE 4 Various Compositions of Film Dosages Buprenorphine Films UnitComponents Formula (mg per film strip) Buprenorphine 8.64 2.16 InactiveComponents Polyethylene Oxide, NF 17.66 21.87 (MW 100,000) PolyethyleneOxide, NF 2.17 2.35 (MW 900,000) Sugar Alcohol 5.43 6.72 Flavor 2.8 2.8HPMC 1.9 2.69 Sweetener 1.2 1.2 Colorant 0.2 0.2 Total (mg) 40 40

Example 5—Cmax and AUCinf Levels for Film Strips IncorporatingBuprenorphine

Five film dosage compositions were prepared, each includingbuprenorphine in a dosage of from 2 mg to 16 mg. Table 5 below setsforth Cmax and AUCinf levels for various dosage levels of filmcompositions including buprenorphine.

TABLE 5 Cmax and AUCinf Levels for Film Strips IncorporatingBuprenorphine Buprenorphine Cmax AUCinf 2 mg 0.7-1.07 ng/ml 6.8-9.5 hr ·ng/ml 4 mg 1.2-1.84 ng/ml 11.2-16.7 hr · ng/ml 8 mg 2.3-3.8 ng/ml22.7-34.1 hr · ng/ml 12 mg 2.8-5.2 ng/ml 30.4-48.6 hr · ng/ml 16 mg4.08-6.4 ng/ml 42.6-65.8 hr · ng/ml

Example 6—Preparation of Films for In Vivo Study

Film dosages were prepared for use in an in vivo study to determine thebioavailability of buprenorphine/naloxone tablets and film formulations.Specifically, the films were tested to determine whether the filmprovides a bioequivalent effect to that of a tablet formulation.

Three film formulations including 8 mg buprenorphine and 2 mg naloxonewere prepared, each being buffered to a different pH. The first film didnot include any buffer, providing a local pH of about 6.5. The secondwas buffered to a local pH level of about 3-3.5. The third was bufferedto a local pH value of about 5-5.5. The formulations are set forth inTable 6 below.

TABLE 6 Formulations of Test Films at Various pH Levels Test formulation1 Test formulation 2 Test formulation 3 8 mg/2 mg 8 mg/2 mg 8 mg/2 mg pH= 6.5 pH = 3-3.5 pH = 5-5.5 Component % w/w Mg/film % w/w Mg/film % w/wMg/film Buprenor- 21.61 8.64 17.28 8.64 17.28 8.64 phine HCl Naloxone6.10 2.44 4.88 2.44 4.88 2.44 HCl Dihydrate Polymer 5.05 2.02 4.82 2.414.82 2.41 Polymer 28.48 11.39 27.09 13.55 27.09 13.55 Polymer 12.65 5.0612.04 6.02 12.04 6.02 Polymer 4.43 1.77 4.22 2.11 4.22 2.11 Sweetener12.65 5.06 12.04 6.02 12.04 6.02 Sweetener 3 1.2 3 1.5 3 1.5 Flavor 62.4 6 3 6 3 Citric acid 0 0 5.92 2.96 2.51 1.26 Sodium 0 0 2.68 1.346.08 3.04 citrate FD&C 0.025 0.01 0.03 0.02 0.03 0.02 yellow #6 Total100 40 100 50 100 50

Example 7—Analysis of In Vivo Absorption of Film Having a pH of 6.5

The film dosage composition of film having a local pH of 6.5 wasanalyzed. Specifically, Test Formulation 1, as prepared in Example 5 wasanalyzed in vivo to determine the absorption of buprenorphine and ofnaloxone. The comparative film was compared to the absorption ofbuprenorphine and of naloxone provided by a one dose tablet (Suboxone®).The test film was compared to determine whether it provided abioequivalent effect as the Suboxone® tablet.

The results for Test Formulation 1, which had a local pH of about 6.5,as compared to the one dose tablet, are set forth in Tables 7 and 8below.

TABLE 7 Buprenorphine In Vivo Absorption Data for Test Formulation 1Test Formulation 1 Suboxone ® sublingual (pH = 6.5) Parameter n Mean SDCV % n Mean SD CV % T_(max) (hr) 15  1.60 0.47 29.41 15  1.50 0.62 41.23C_(max) 15  2.27 0.562 24.77 15  2.60 0.872 33.53 (ng/mL) AUC_(last) 1527.08 10.40 38.41 15 31.00 12.93 41.72 (hr * ng/mL) AUC_(inf) 15 29.5811.15 37.68 15 33.37 13.88 41.61 (hr * ng/mL) T_(1/2) (hr) 15 44.7620.86 46.60 15 40.73 14.93 36.66

TABLE 8 Naloxone In Vivo Absorption Data for Test Formulation 1 TestFormulation 1 Suboxone ® sublingual (pH = 6.5) Parameter n Mean SD CV %n Mean SD CV % T_(max) (hr) 15 0.90 0.23 25.32 15 0.68 0.18 25.75C_(max) 15 94.6 39.1 41.33 15 410 122 29.75 (pg/mL) AUC_(last) 15 297.1120.7 40.62 15 914.8 158.1 17.29 (hr * pg/mL) AUC_(inf) 15 306.1 122.640.06 15 924.2 158.8 17.18 (hr * pg/mL) T_(1/2) (hr) 15 6.62 2.60 39.2615 6.86 2.08 30.27

As can be seen, the in vivo data indicates that buprenorphine isabsorbed very well from the film formulation at a local pH of 6.5, andmatched closely the absorption seen in the Suboxone® one dose tablet.However, the absorption was also maximized for the naloxone, which wasundesirable. It was determined that a film having a combination ofbuprenorphine and naloxone and a local pH of 6.5 did not provide abioequivalent effect as the one dose Suboxone® tablet for bothbuprenorphine and naloxone.

Example 8—Analysis of In Vivo Absorption of Film Having a pH of 5-5.5

Having determined the absorption of buprenorphine and naloxone in filmhaving a local pH of 6.5, a film dosage composition of film having alocal pH of 5-5.5 was analyzed. Specifically, Test Formulation 3, asprepared in Example 5 was analyzed in vivo to determine the absorptionof buprenorphine and of naloxone. The comparative films were compared tothe absorption of buprenorphine and of naloxone provided by a one dosetablet (Suboxone®). The test film was compared to determine whether itprovided a bioequivalent effect as the tablet product.

The results for Test Formulation 3, which had a local pH of about 5-5.5,as compared to the one dose tablet, are set forth in Tables 9 and 10below.

TABLE 9 Buprenorphine In Vivo Absorption Data for Test Formulation 3Test Formulation 3 Suboxone ® sublingual (pH = 5-5.5) Parameter n MeanSD CV % n Mean SD CV % T_(max) (hr) 15  1.60 0.47 29.41 14  1.50  0.4328.50 C_(max) 15  2.27 0.562 24.77 14  3.47  1.57 45.40 (ng/mL)AUC_(last) 15 27.08 10.40 38.41 14 33.25 16.01 48.16 (hr * ng/mL)AUC_(inf) 15 29.58 11.15 37.68 13 38.34 15.38 40.13 (hr * ng/mL) T_(1/2)(hr) 15 44.76 20.86 46.60 13 41.71 17.70 42.42

TABLE 10 Naloxone In Vivo Absorption Data for Test Formulation 3 TestFormulation 3 Suboxone ® sublingual (pH = 5-5.5) Parameter n Mean SD CV% n Mean SD CV % T_(max) (hr) 15 0.90 0.23 25.32 14 0.98 0.62 63.51C_(max) 15 94.6 39.1 41.33 14 173 84.5 48.79 (pg/mL) AUC_(last) 15 297.1120.7 40.62 14 455.2 195.5 42.94 (hr * pg/mL) AUC_(inf) 15 306.1 122.640.06 13 474.4 203.1 42.81 (hr * pg/mL) T_(1/2) (hr) 15 6.62 2.60 39.2613 9.45 6.90 73.00

As can be seen, the in vivo data indicated that the absorption ofbuprenorphine increased as the local pH level decreased. It appearedthat by decreasing the local pH from 6.5 to 5.5, the absorption ofbuprenorphine was being moved to a level much greater than that of theone dose Suboxone® tablet. In addition, the naloxone values did notprovide a bioequivalent result as the one dose tablet. Thus, it wasdetermined that the film having a local pH of 5.5 did not provide abioequivalent result as that of the Suboxone® tablet for bothbuprenorphine and naloxone.

It was noted that by reducing the local pH of the film to a level of5.5, there would be provided an increased level of absorption ofbuprenorphine. Thus, it may be desirable to buffer a film compositionincorporating buprenorphine itself to a level of about 5.5 to provide anincreased absorption.

Example 9—Analysis of In Vivo Absorption of Film Having a pH of 3-3.5

Having determined the absorption of buprenorphine and naloxone in filmshaving a local pH of 6.5 and 5.5, a film dosage composition of filmhaving a local pH of about 3-3.5 was analyzed. It was assumed that theabsorption of buprenorphine would continue to be increased as it haddemonstrated at a local pH of 5.5. Thus, it was assumed that at a localpH of 3.5, the film would not be bioequivalent to that of the tablet.

Specifically, Test Formulation 2, as prepared in Example 5, was analyzedin vivo to determine the absorption of buprenorphine and of naloxone.The comparative films were compared to the absorption of buprenorphineand of naloxone provided by a one dose tablet (Suboxone®). The test filmwas compared to determine whether it provided a bioequivalent effect asthe tablet product.

The results for Test Formulation 2, which had a local pH of about 3-3.5,as compared to the one dose tablet, are set forth in Tables 11 and 12below.

TABLE 11 Buprenorphine In Vivo Absorption Data for Test Formulation 2Test Formulation 2 Suboxone ® sublingual (pH = 3-3.5) Parameter n MeanSD CV % n Mean SD CV % T_(max) (hr) 15  1.60 0.47 29.41 14  1.68 0.5834.68 C_(max) 15  2.27 0.562 24.77 14  2.68 0.910 33.99 (ng/mL)AUC_(last) 15 27.08 10.40 38.41 14 29.73 12.05 40.54 (hr * ng/mL)AUC_(inf) 15 29.58 11.15 37.68 14 31.45 12.98 41.26 (hr * ng/mL) T_(1/2)(hr) 15 44.76 20.86 46.60 14 30.03 13.95 46.46

TABLE 12 Naloxone In Vivo Absorption Data for Test Formulation 2 TestFormulation 2 Suboxone ® sublingual (pH = 3-3.5) Parameter n Mean SD CV% n Mean SD CV % T_(max) (hr) 15 0.90 0.23 25.32 14 0.84 0.19 22.19C_(max) 15 94.6 39.1 41.33 14 130 72.9 56.04 (pg/mL) AUC_(last) 15 297.1120.7 40.62 14 362.2 155.9 43.03 (hr * pg/mL) AUC_(inf) 15 306.1 122.640.06 12 350.4 142.3 40.61 (hr * pg/mL) T_(1/2) (hr) 15 6.62 2.60 39.2612 8.07 4.75 58.84

As can be seen, the in vivo data indicated that the absorption ofbuprenorphine was substantially bioequivalent to that of the one dosetablet when the film composition local pH was lowered to about 3-3.5.This result was surprising as it did not appear to follow the pHpartition theory. Further, at a local pH of about 3-3.5, it was seenthat the absorption of naloxone was substantially bioequivalent to thatof the one dose tablet.

Thus, it was determined that the film product including buprenorphineand naloxone at a local pH of 3-3.5 was substantially bioequivalent tothat of the Suboxone® one dose tablet. It was therefore evident that onecould formulate the naloxone at a local pH of 3.5 or lower to inhibitits absorption, and formulate the buprenorphine at a local pH of about5.5 to optimize its absorption.

Example 10—Normalized Values for Naloxone in Films and Tablets

Various film compositions including buprenorphine and naloxone in 8/2 mgand 2/0.5 mg dosages, and having different local pH values from 6.5 to3.5, were prepared and analyzed. The data was normalized and compared tothe one dose Suboxone® tablet. The results are set forth in Table 13below.

TABLE 13 Normalized Values for Naloxone Film Compared to Tablet RatioCitric Dose (mg) Mg Acid (mg)/ Buprenorphine/ AUC Citric Naloxone pHNaloxone (Normalized) Cmax Acid (mg) 6.5 8/2 3.02 4.33 1.34 0.67 5.5 8/21.55 1.83 1.34 0.67 3.5 8/2 1.14 1.37 1.34 0.67 3.5  2/0.5 0.98 0.901.34 2.68 5.5  2/0.5 1.41 1.41 1.34 2.68

The data indicates that not only is the local pH of significantimportance, but the amount of acid present in the formula is alsoimportant. The improvement from the 8/2 dose to the 2/0.5 dose (at alocal pH of 3.5) demonstrates this importance. The 8/2 dose has a ratioof acid/naloxone of 0.67, and this dose provided borderline acceptablebioequivalent results. In contrast, the 2/0.5 dose has a ratio ofacid/naloxone of 2.68 at a local pH of 3.5, and provides a morebioequivalent absorption value than the 8/2 dose.

In fact, the data shows that the 2/0.5 dose at a local pH of 3.5 had aneven lower buccal absorption than the one dose tablet, as seen from thenormalized values for the AUC and Cmax. This demonstrates that even lessabsorption of the naloxone occurs for the film formulation at a local pHof 3.5 than the tablet formulation. Given the goal of reducing theabsorption of naloxone, it appears that the film product buffered at alocal pH of 3.5 with a buffer ratio (buffer/naloxone) of 2.68 provideseven better results than the Suboxone® formulation.

Example 11—Absorption Data for Dual-Film Dosage at Local pH 3.5 andLocal pH 5.5

A dual-film dosage is prepared, with the first film layer having a localpH of about 3.5 and containing an antagonist therein, and the secondfilm layer having a local pH of about 5.5 and containing an agonisttherein. In this dual-film dosage, the first film layer (having theantagonist) is a fast-dissolving film, while the second film layer(having the agonist) is a moderate dissolving film. Using data from theabove studies, absorption levels for various amounts of product in thefilm is presented in Table 14 below:

TABLE 14 Extrapolated Absorption Data for Dual-Layered Film at AgonistLocal pH of 3.5 and Naloxone Local pH of 5.5 Dose (mg agonist/ NaloxoneNaloxone AUC mg naloxone) Cmax (pg/ml) (hr*pg/ml)  2/0.5 32.5 90.5 8/2130 362 16/4  260 724

Therefore, at amounts of 0.5-4.0 mg, the Cmax level for the Naloxone isbetween about 32.5 to about 260 pg/ml and the AUC for the Naloxone isbetween about 90.5 to about 724 hr*pg/ml. As will be understood, varyingtypes and levels of buffers may increase or decrease the absorptionvalues. That is, when seeking to inhibit the absorption of theantagonist (i.e., naloxone), one may select a particular local pH forthe agonist region and a second local pH for the antagonist region. Thelocal pH of the region may depend on the amount of active included inthat region. The amounts of actives incorporated into the dosage may bealtered to provide suitable absorption levels, and may include amountsin milligrams, nanograms, picograms, or any desired amount of active.

Example 12—Comparison of Antioxidants and Stabilizing Agents on theStability of Naloxone in a 8/2 mg (Buprenorphine/Naloxone) FilmFormulation

Lab scale batches of 8/2 mg (Buprenorphine/Naloxone) film dosage unitscontaining the following excipients were produced as previouslydescribed:

1. Ascorbic Acid 2. EDTA (Ethylenediaminetetraacetic Acid Disodium Salt)3. BHT (Butylated Hydroxytoluene) 4. Propyl Gallate

5. Sodium sulfite

6. Citric Acid 7. Sodium Metabisulfite

8. Stabilizer System containing Ascorbic Acid, EDTA, Sodiummetabisulfite, BHT.

Samples were stored for 4 weeks at 60° C. and a relative humidity of57%. The amounts of naloxone and oxidation products of naloxone,5-hydroxy naloxone (5HN), naloxone n-oxide (NNO), and noroxymorphone(NOMP) were then determined. The results are reported in Table 15:

TABLE 15 4 Week Stability Naloxone/Antioxidant Study % Naloxone % 5HN %NNO % NOMP 4 4 4 4 Sample No. Initial Weeks Initial Weeks Initial WeeksInitial Weeks Control 109.9 101.2 0.1723 0.910 0.0260 ND 0.1358 0.64Ascorbic 1 104.7 94.3 0.0908 0.44 ND ND 0.1115 0.16 Acid EDTA 2 105.6102.0 0.0385 0.18 0.0028 ND 0.1262 0.17 BHT 3 105.3 100.4 0.0906 0.86 NDND 0.1365 0.30 Propyl 4 102.6 97.7 0.3057 0.90 ND ND 0.1565 0.25 GallateNa 5 104.7 98.1 0.0991 1.14 0.0035 ND 0.1318 0.53 Sulfite Citric 6 105.198.1 0.1208 1.38 ND ND 0.1374 0.66 Acid Na 7 64.2 55.8 0.0395 0.12 ND ND0.3855 2.47 Metabi- Sulfite Stabilizer 8 112.3 105.1 0.0466 0.01 ND ND0.1482 0.91 System

The addition of the stabilizer system and EDTA had a positive impact onthe production of 5HN. The addition of sodium sulfite, BHT, citric acidand propyl gallate had no improvement over control.

The addition of EDTA results in a reduction of 5HN from 0.91% to 0.18%after 4 weeks storage at 60° C. and 75% relative humidity. Thus, EDTAappears to be effective in stabilizing naloxone in the filmcompositions.

Example 13—EDTA Concentration Study

The appropriate EDTA level to protect naloxone from oxidation when usedin the formulation of the 8/2 mg (buprenorphine/naloxone) film wasstudied. Samples of the 8/2 mg (buprenorphine/naloxone) films wereproduced with following amounts of EDTA: 4.0 mg, 2.0 mg, 1.0 mg, 0.2 mg,and no EDTA (control).

The samples were stored at 60° C. and 75% relative humidity for 4 weeksand the combined content of 2 primary oxidation product, 5HN and NNO wasdetermined initially, at 2 weeks, and at 4 weeks for each formula. Theresults are reported in FIG. 1.

Based on the incremental differences observed in the summed levels of5HN and NNO between the 2 mg EDTA sample and the 1 mg EDTA sample, a 1mg level of EDTA is sufficient to significantly reduce oxidation ofnaloxone in the film product.

What is claimed is:
 1. A self-supporting film dosage compositioncomprising: a. a polymeric carrier matrix; b. a therapeuticallyeffective amount of an agonist or a pharmaceutically acceptable saltthereof; c. a therapeutically effective amount of an antagonist or apharmaceutically acceptable salt thereof; and d. a chelator orantioxidant; wherein the ratio of said antagonist to said chelator orantioxidant is from about 40:1 to about 1:10 by weight.
 2. Thecomposition of claim 1, wherein said ratio of said antagonist to saidchelator or antioxidant is from about 4:1 to about 1:10 by weight. 3.The composition of claim 1, wherein said ratio of said antagonist tosaid chelator or antioxidant is from about 5:1 to about 1:2 by weight.4. The composition of claim 1, wherein said ratio of said antagonist tosaid chelator or antioxidant is from about 1:2 to about 2:1 by weight.5. The composition of claim 1, wherein said chelator or antioxidant isselected from the group consisting of ethylenediaminetetraacetic acid(EDTA) and salts thereof, proteins, polysaccharides, polynucleic acids,glutamic acid, histidine, organic diacids, polypeptides, phytochelatin,hemoglobin, chlorophyll, humic acid, phosphonates, transferrin,desferrioxamine, dibutylhydroxytoluene (BHT), dibutylated hydroxyanisole(BHA), propyl gallate, sodium sulfate, citric acid, sodiummetabisulfite, ascorbic acid, tocopherol, tocopherol ester derivatives,2-mercaptobenzimidazole, and combinations thereof.
 6. The composition ofclaim 1, wherein said chelator or antioxidant isethylenediaminetetraacetic acid disodium salt.
 7. The composition ofclaim 1, wherein said antagonist is naloxone or a pharmaceuticallyacceptable salt thereof.
 8. The composition of claim 1, wherein saidagonist is buprenorphine or a pharmaceutically acceptable salt thereof.9. The composition of claim 1, wherein said antagonist is naloxone or apharmaceutically acceptable salt thereof and said agonist isbuprenorphine or a pharmaceutically acceptable salt thereof.
 10. Thecomposition of claim 1, wherein said composition comprises a firstregion and a second region, said first region comprising said agonistand said second region comprising said antagonist.
 11. A self-supportingfilm dosage composition comprising: a. a polymeric carrier matrix; b. atherapeutically effective amount of buprenorphine or a pharmaceuticallyacceptable salt thereof; c. a therapeutically effective amount ofnaloxone or a pharmaceutically acceptable salt thereof; and d. achelator or antioxidant; wherein the ratio of said naloxone or apharmaceutically acceptable salt thereof to said chelator or antioxidantis from about 40:1 to about 1:10 by weight.
 12. The composition of claim11, wherein said ratio of said naloxone or a pharmaceutically acceptablesalt thereof to said chelator or antioxidant is from about 4:1 to about1:10 by weight.
 13. The composition of claim 11, wherein said ratio ofsaid naloxone or a pharmaceutically acceptable salt thereof to saidchelator or antioxidant is from about 5:1 to about 1:2 by weight. 14.The composition of claim 11, wherein said ratio of said naloxone or apharmaceutically acceptable salt thereof to said chelator or antioxidantis from about 1:2 to about 2:1 by weight.
 15. The composition of claim11, wherein said chelator or antioxidant is selected from the groupconsisting of ethylenediaminetetraacetic acid (EDTA) and salts thereof,proteins, polysaccharides, polynucleic acids, glutamic acid, histidine,organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll,humic acid, phosphonates, transferrin, desferrioxamine,dibutylhydroxytoluene (BHT), dibutylated hydroxyanisole (BHA), propylgallate, sodium sulfate, citric acid, sodium metabisulfite, ascorbicacid, tocopherol, tocopherol ester derivatives, 2-mercaptobenzimidazoleand combinations thereof.
 16. The composition of claim 11, wherein saidchelator or antioxidant is ethylenediaminetetraacetic acid disodiumsalt.
 17. The composition of claim 11, further comprising a buffer in anamount sufficient to maximize the absorption of the buprenorphine or apharmaceutically acceptable salt thereof.
 18. The composition of claim11, further comprising a buffering system comprising a buffer capacitysufficient to inhibit the absorption of said naloxone or apharmaceutically acceptable salt thereof during the time which saidcomposition is in the oral cavity of a user.
 19. The composition ofclaim 11, wherein said composition comprises a first region and a secondregion, said first region comprising said buprenorphine or apharmaceutically acceptable salt thereof and said second regioncomprising said naloxone or a pharmaceutically acceptable salt thereof.20. The composition of claim 11, wherein said buprenorphine or apharmaceutically acceptable salt thereof has a local pH of about 3 toabout 9.